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dc.contributor.authorNeckmann, Ulrike
dc.contributor.authorWolowczyk, Camilla
dc.contributor.authorHall, Martina
dc.contributor.authorAlmaas, Eivind
dc.contributor.authorRen, Jiang
dc.contributor.authorZhao, Sen
dc.contributor.authorJohannessen, Bjarne
dc.contributor.authorSkotheim, Rolf I.
dc.contributor.authorBjørkøy, Geir
dc.contributor.authorDijke, Peter Ten
dc.contributor.authorHolien, Toril
dc.description.abstractBackground In breast cancer, activation of bone morphogenetic protein (BMP) signaling and elevated levels of BMP-antagonists have been linked to tumor progression and metastasis. However, the simultaneous upregulation of BMPs and their antagonist, and the fact that both promote tumor aggressiveness seems contradictory and is not fully understood. Methods We analyzed the transcriptomes of the metastatic 66cl4 and the non-metastatic 67NR cell lines of the 4T1 mouse mammary tumor model to search for factors that promote metastasis. CRISPR/Cas9 gene editing was used for mechanistic studies in the same cell lines. Furthermore, we analyzed gene expression patterns in human breast cancer biopsies obtained from public datasets to evaluate co-expression and possible relations to clinical outcome. Results We found that mRNA levels of the BMP-antagonist Grem1, encoding gremlin1, and the ligand Bmp4 were both significantly upregulated in cells and primary tumors of 66cl4 compared to 67NR. Depletion of gremlin1 in 66cl4 could impair metastasis to the lungs in this model. Furthermore, we found that expression of Grem1 correlated with upregulation of several stem cell markers in 66cl4 cells compared to 67NR cells. Both in the mouse model and in patients, expression of GREM1 associated with extracellular matrix organization, and formation, biosynthesis and modification of collagen. Importantly, high expression of GREM1 predicted poor prognosis in estrogen receptor negative breast cancer patients. Analyses of large patient cohorts revealed that amplification of genes encoding BMP-antagonists and elevation of the corresponding transcripts is evident in biopsies from more than half of the patients and much more frequent for the secreted BMP-antagonists than the intracellular inhibitors of SMAD signaling. Conclusion In conclusion, our results show that GREM1 is associated with metastasis and predicts poor prognosis in ER-negative breast cancer patients. Gremlin1 could represent a novel target for therapy.nb_NO
dc.rightsNavngivelse 4.0 Internasjonal*
dc.titleGREM1 is associated with metastasis and predicts poor prognosis in ER-negative breast cancer patientsnb_NO
dc.typeJournal articlenb_NO
dc.typePeer reviewednb_NO
dc.source.journalCell Communication and Signalingnb_NO
dc.relation.projectStiftelsen Kristian Gerhard Jebsen: SKGJ-MED-015nb_NO
dc.relation.projectKreftforeningen: 63825nb_NO
dc.relation.projectNorges forskningsråd: 223255nb_NO
dc.relation.projectKreftforeningen: 63843nb_NO
dc.description.localcode© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver( applies to the data made available in this article, unless otherwise stated.nb_NO
cristin.unitnameInstitutt for bioingeniørfag
cristin.unitnameInstitutt for klinisk og molekylær medisin
cristin.unitnameLaboratoriemedisinsk klinikk
cristin.unitnameInstitutt for bioteknologi og matvitenskap
cristin.unitnameInstitutt for samfunnsmedisin og sykepleie
cristin.unitnameMedisinsk klinikk

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